Tertiary-aminoalkyl 4-amino-2-hydroxy-benzoates, their salts and preparation thereof



United States PatentO TERTIARY ANHNOALKYL 4-AlVIINO-2-HYDROXY- BENZOA'IEQTHER SALTS AND PREPARATION THEREOF Raymond G. Glinton; North- Greenbush, and Stanley C. Laskowski, Menands, N. Y.,, assignors to Sterling Drug Inc., New York, N. Y., a corporation of Delaware No Drawing. Application October 9, 1953, Serial No. 385,281

20 Glaims. (CL. 260-2943) This application relates to tertiary-aminoalkyl esters of 4-amino-2-hydroxybenzoic acid, to water-soluble acid-addition salts thereof, and tothe preparation of these new compounds.

We have found that thebasic-esterscof the general formula where X is a lower alkylene radical and NRR' is'a-lower aliphatic-like tertiary-amino radical, exhibit valuable pharmacological properties. .These esters preferably in their form of water-soluble acid-addition salts, haveibeen found to possess outstanding local. anesthetic activity. These esters arealso useful in that as bases. they form salts with penicillin which have a valuable protracted antibiotic activity [Kiel et a1., Arzneimittel-Forsch. 1', 326 (1951) This application is a continuation-in-part of our application Serial Number 168,841, filed June 17, 1950, now abandoned. Since the filing of our parent application, W. Keil et a1. [Arzneimittel-Forsch. 1, 154-6 and 270 (1951); ibid., 2, 112 (1952)] and Grimme and Schmitz [Ben 84, 734 (1951).] have also described the compounds disclosed and claimed in our said parent and present applications.

Inthe above general formula, the lower alkyleneradical represented by X has preferably 2-4 carbon atoms, and has its two free valence bonds on different carbon atoms.

Thus X includes such examples as -CHaCHzCH2CH2-, CH2CH(CH3)CHz-, and the like. Thelower aliphaticdike tertiary-amino: radical shown above as NRR' comprehends-lower'gdialkylamino radicals where R and R'- are lower alkylgroups, alike or different, and. each alkyl group havingypreferably I-6 carbon atoms, such dialkylaminoradicals includingdimethylamino, diethylamino, ethylmethylaminm. diisopropylamino, di-n-butylamino, di-nrhexylamino and-.the like. Further, the lower aliphatic-like. tertiary-amino radical designated as NRR! encompasses thosez radicals where. R and R are joined directly or through arr-oxygen atom to'form saturated N-heteromonocyclic radicalsshaving -6 ring atoms, illustrated by examples such as 1- pipcridyl, 2-methyl-l-piperidyl, S-ethyl-l-piperidyl, 4- methyl-l-piperidyl, 2,6-dimethy1-1-piperidyl',- I-pyr'rolidyl,

'ice :2. 2 '-me"thyI- 1-pyrro'lidyl; 2,5 dimethyl-1-pyrrolidy1,- 4-morpholinyl, and the like.

above basic esters are'prcpared by esterifying 4- ni'trb-Z-hydroxybenzoic acid to produce the tertiary-aminoalkyl 4'-nitro-2 hydroxybenzoate having the formula where X andNRR. have. themeanings given. hereinabove, and reducing said. basic 4-nitro-2-hydroxybenzoate to athfi. corresponding vtertiary-aminoalkyl 4-amino 2-hydroxybenzoate. A specific illustration of this procedure is the tormation. of Z-dihaethylaminoethyl A-amino-Lhydroxyhenzoate ;by esterifying -4-nitro-2hydr'oxyben2oic acid. to produce 2.-dirnethylaminoethyl 4-nitro-2-hydroxyhenzoate .and-.re.ducing.,.the latter. to form 2 dimethyl'- amirioethyl A-aniino-Z-liydroxybenzoate. We carriedout the esten'ficationof 4.-nitro-,2-hydroxybenzoic acid to. produce the corresponding tertiary-.amihoalkyl ester. in various ways, In. one procedure, the 4,-nitro-2-hydroxybnzoic acid was reacted with a tertiary aminoalkyl halide. In another procedure, alower alkyl 4-nitro-2-hydroxybenzoate was-transesterified with a tertiary-aminoalkanol. In" still another procedure, the 4-nitro-2-hydroxybenzoic acid 'was first treated with a haloal'kanol to produce a haloa lkylester whichwas reacted with a secondary amine toyield the desired tertiar'y-aminoalkyl ester. Thus; in the above specific illustration-,- -2-ditnethyl'arninoethyl 4- nitrb-Lhydroxybenzoate: is prepared :by reacting 4-nitro- 2-hydroxybenzoic acid with Z-dimethylaminoethylxchloride; ,by reacting methyl 4-nitro-2-hydroxybenzoate with Z-dimethyl-aminclethanol; or by first reacting 4-nitro-2 -hydroxybenzoic: acid withethylene chlorohydrin and treat.- ingtheresulting 2.-chloroethy1 4-nitro-2-hydroxybenzoate with ,dimethylamine.

.The redu,ction of the -tertiary-aminOalkyl 4-nitro-2- hydroxybenzoates to the corresponding 4-an'1ino-.2 -hydroxybenzoates was carried out both by chemical methods and'by catalytic hydrogenation. Suitable chemical re.- ducing agents include iron and hydrochloric acid, ferrous sulfate and ammonia, tin and hydrochloric acid, sodium h ydrosulfite, etc. Catalysts suitable when catalytic hydrogenation' isused include Raney nickel, platinum, palladium or other catalysts generally effective to catalyze hydrogenation of nitro groups to amino groups.

"Our tertiary-aminoalkyl- 4-amino-2-hydroxybenzoates are-therapeutically active whether employed as the free bases or as-their salts with relatively non-toxic organic or.-,inorganic acids. We found it convenient to isolate the-basic esters as their hydrochlorides or phosphates. However, other acid-addition salts are withinthe scope of our; invention. Such additional, salts include the hydrobrornides, sulfates, citrates, sulfamates, tartrates, ,su'ccinates, acetates, benzoates, oleates, and the like.

Specific embodiments of our invention are illustrated in the following paragraphs:

(l) Tertiary-'aminoalkyl 4-nitro-Z-hydroxybenzoates tertiary-aminoalkyl halide; by the reaction of a lower alkyl '4-nitro-2-hydroxybenzoate' with a tertiary-amino alkanol; or by the reaction of 4-nitro-2-hydroxybenzoic acid with a haloalkanol followed by treatmentofthe re.- sulting haloalkyl ester with a secondary amine. p

. The first variant is illustrated bythe following preparation of Z-diethylarninoethyl 4-nitro- 2-hydroxybenzoate hydrochloride: To a stirred refluxing solution of 137 .5 g. of

4-nitro-2-hydrobenzoic acid in 800 ml. of isopropanol was added dropwise 110 g. of 2-diethylaminoethyl chloride during the course of one and one-half hours. The resulting heterogeneous mixture was stirred and refluxed for an additional seven hours, cooled, and the dense white precipitate was collected. The filter was evaporated to dryness in vacuo and the resulting residue was triturated with acetone. The acetone-insoluble material was combined with the original precipitate and the material was recrystallized several'times from ethanol in the presence of a small amount of anhydrous hydrogen chloride. There was obtained 161.4 g. (67.7%) of Z-diethylaminoethyl 4-nitro-2-hydroxybenzoate hydrochloride, M. P. 179.6- 180;4 C. (corn), crystallizing in .whitefneedles.

The second procedure of reacting a lower alkyl 4-nitro- LZ-hydroxybenzoate with a tertiary-aminoalkanol is illustrated by the following preparation of 3-(2-methyl-1- piperidyl)propyl 4-nitro-2-hydroxybenzoate hydrochloride: A mixture of 84.5 g. of ethyl 2-hydroxy-4-nitrobenzoate, 70.8 g. of 3-(2-methyl-1-piperidyl)propanol, 700 ml. of dry toluene and 200 mg. of sodium methoxide was slowly distilled through an efficient ,fractionating column. The evolution of ethanol was slow,"requiring "forty-eight hours for completion. The residue was evap- 'orated in vacuo and the resulting viscous oil was dis- 'solved in ethyl acetate and treated with an excess of ethereal hydrogen chloride. The resulting thick heavy oil Was separated by decantation and dissolved in dry acetone. On scratching and cooling this solution a dense white .precipitate appeared. Several recrystallizations from isopropanol gave 55.7 g. (39%) of 3-(2-methyl-1- piperidyl)propyl 4-nitro-2-hydroxybenzoate hydrochloride, crystallizing in needles, M. P. 173.0.-173.8 C. (60113).

The third variant for preparing the tertiary-aminoalkyl 4-nitro-Zhydroxybenzoates is illustrated as follows:' A mixture of one mole of 4-nitro-2-hydroxybenzoic acid and three moles of ethylene chlorohydrin was heated to reflux and dry hydrogen chloride was passed into the reaction mixture for eight hours. The excess ethylene chlorohydrin was removed by distilling in vacuo and the residue when crystallized from absolute ethanolyielded 2-chloroethyl 4-nitro Z-hydroxybenzoate, M. P. 87.488.4

C. (corn). The corresponding 2-bromoethyl ester, M. P -E 74.7-74.9 C. (corn), resulted when ethylene bromohydrin was used in place of ethylene chlorohydrin; A mixture of one mole of 2'chloroethyl (or 2-brornoethyl) 4-nitro-2-hydroxybenzoate and two moles of diethylamine hours. After removal of the solvent by distilling. in vacuo, the residue was dissolved in hydrochloric acid, the acidic solution was treated with decolorizing charcoal and and 1500 ml. of toluene was refluxed for twenty-four filtered. The filtrate was made alkaline with potassium carbonate and the mixture wasextracted, with ethyl acetate. After removal of the ethyl acetate byidistilling in vacuo, the residue was dissolved in absolute ethanol and the alcoholic solution was treated with excess hydrogen chloride in ether. Addition of excess ether "precipitated the basic ester salt, 2-diethylaminoethyl 4-nitro-2-hydroxybenzoate hydrochloride, which was recrystallized from isopropanol. 7

Other tertiary-aminoalkyl 4-nitro-2-hydroxybenzoate hydrochlorides prepared according to the foregoing pro- I cedures include those given in Table A. j

TABLE A NO:

M. P./ C. NRR (corn) 2 N (CH3): 174. 0-175. 0 2 NCsHio 183. 8-184. 8 2 NGsHu 181. 5-182. 2 2 NG7H14 181. 5-182. 1 3 NCsHm 183. 0-184. 0 2 Nc H o 195. 2-197. 6 3 NOlHSO 210. 0-210. 6

Z-hydroxybenzoate hydrochloride; 2-( l-pyrrolidyl)ethyl- 4-nitro-2-hydroxybenzoate hydrochloride; 3-(2-methyl-1- pyrrolidyl)propyl 4-nitro-2-hydroxybenzoate hydrochloride; and 2-(2,5-dimethyl-l-pyrrolidyl)ethyl 4-nitro-2- hydroxybenzo'ate hydrochloride. 1

The corresponding free bases of the foregoing salts, i. e., the tertiary-aminoalkyl 4-nitro-2-hydroxybenzoates, are highly-colored, high melting solids soluble in polar solvents such as water, methanol, ethanol, etc. and in- .soluble in non-polar solvents. They probably have the structure of inner salts, with the formula 2) T ertiary-aminoalkyl 4 amino 2 hydroxybenzoates These esters are prepared by reducing the hereinabove described tertiary-aminoalkyl 4-nitro-2-hydroxybenzoates. This reduction is carried out either by chemical means or by catalytic hydrogenation methods.

Exemplary of the chemical method is the following preparation of 2-(2,6-dimethyl-l-piperidyl)ethy 4-amino- '2-hydroxybenzoate: To a stirred boiling mixture of 90 g.. "of iron powder, 200 ml. of water, 300 ml. of ethanol and 1 ml. of concentrated hydrochloric acid was gradually addedin portions 80.7 g. of 2-(2,6-dimethyl-l-piperidyl)- Jethyl 2-hydroxy-4-nitrobenzoate hydrochloride. Each addition produced an exothermic recation. When the addition had'been completed, the mixture was stirred at the boiling point for twenty minutes. ring and heating, 30 to 40 g. of solid sodium bicarbonate While continuing stirwas cautiously added, and the resulting mixture was stirred .and heated an additional ten minutes. The mixture was filteredhot and the filter cake washed well with hot ethanol. The combined filtrates were concentrated in vacuo until all ethanol was removed. The residualfaque- I pus suspension: of the crystalline base was cooled and :s e filtered, and the precipitate was washed well with cold M water. The precipitate crystallized from n-heptane in MRleocom) rosettes of beautiful long slender needles of 2-(2,6-dimethyl v l-piperidyDethyl 4-amino 2 hydroxybenzoate, M. P. Base Phosphate 111.0111.6 C. (com). The phosphate of this basic N V, v, ester was prepared from mole equivalents of base and 2 mom), 13614312 21934200.: phosphoric acid (HsPO4) in absolute ethanol and recrys- 2 M01115): l 54-045 -8: tallized by dissolving in a minimum amount of hot water, b 2318:2218 25%; 33213 filtering and slowly diluting with hot absolute ethanol. M 133): .011 mac-210.7: The resulting salt, 2-(2,6-dimethyl-l-piperidyl)ethyl 1o egfigggt 55 git-33%;; 2 NGHO 4 amigo 2 hydroxybenzoate phosphate, melts at 197.7 3 i S d 231 fgggjg; 200-0 3 metal), 011 212.3

A specific illustration of the catalytic hydrogenation 7 method of preparing our tertiary-aminoalkyl t-amino-Z- hydroxybenzoates is the following synthesis of 3-(1- 2 =2-m fih i e i piperidyl )pro pyl 4eamino-2 hydroxybenzoate: A mixture mgi gggfifigfi f CH(OH3)CHN(CH3)' or of 10.0 g. of 3-(1-piperidyl)propyl 4+nitro-2-hydroxyben- &1 c4flio=4rmqrphunyl 1th decomposition. zoate hydrochloride, 500 mg. of platinum oxide and 150 Monohydrochloride melts at 22511-225? .0. (corn). ml. of 50% aqueous ethanol was hydrogenated in a Parrd 5$ hY QgDB a 5 C- and 50 lbs. pres- 0 M dil t ethanol as the monohydrate, The theofetlcal zfmol-lflt 0f yd qg Was w Additional tertiary-aminoalkyl 4-amino-2-hydroxybenen 0 iwellty m The IIIIXWIB W38 filtered zoates which can be prepared according to the above evaporated t0 dryness in vacuo. T resi White procedures include the following: 4-dimethylaminool w s ys e m e h to give a g yield butyl 4 amino -2 .-hydroxybenzoate; Z-di-n-butylarnino- 0f -P P YUP PY 4-am1n0Qhydrfiybenloate 31- ethyl 4-amino-2-hydroxybenzoate; Z-di-mhexylaminoethyl drochloflde,

C- The P 4-amino-2-hydroxybenzoate; 4-(l-piperidyl)butyl 4-amiphate salt of this basic ester was prepared as follows: nO-Z-llydroxybenzoate; 2 1 1id 1 1 4 i .2 -l P YDP PY 4-am1I1O-Z-hYdIOIfYbBHZOHtB y hydroxybenzoate; 3-(Z-methyl-l-pyrrolidyl)propyl 4-ami- Chlorlde was converted t0 the c y a base y no-Z-hydroxybenzoate; and 2-(2,5-dimethyl-1-pyrrolidyl) ment of an aqueous solution thereof with an excess of soethyl 4 i g b diurn carbonate solution. The resulting base when treated The fo i i i 1k 1 4 i g with a one mole proportion of .85 phosphoric acid in benzoates are also conveniently prepared from 4-nitro-2- absolute alcohol solution readily yielded 3-(l-piperdy1)- hydroxybenzoic acid or its lower alkyl asters through the propyl 4-amino-2-hydroxybenzoate phosphate, forming Z-benzyloxy derivatives according to the steps illustrated rosettes of large blunt needles from 95% ethanol, P. 35 in the following equations, wherein R is a lower alkyl 204.7. -205l0" C. (dec.) (corn). group and X and NRR' have the meanings given herein- Other tertiary-aminoalkyl 4-amino-2-hydroxybenzoates above-z N02 Ifo:

OH OCHzCeH;

l C 0 OH 00 CH 0 H II t t No OCHzCsHs NO NO 0H DCHaClHs. 1111 7 00B" C 00R" 4---- Q-- OH OCHQCQH: OCHzCaH 0 0-X-NRR' C 0 OX-NRR' C 0 OX--NBR' prepared according to the above procedures include those Thus, 4-nitro-2-benzyloxybenzoic acid (B) is prepared given in Table B. TABLE B either by benzylating 4-nitro-2-hydroxybenzoic acid (step I) to form benzyl 4-nitro-2-benzyloxybenzoate (A), which is saponified in step II to yield the desired 4-nitro-2-benzyloxybenzoic acid or by benzylating a lower alkyl 4-nitro- Z-hydroxybenzoate (step I) to form a lower alkyl 4-nitro 0H 2-benzyloxybenzoate (A'), which in step II is saponified to the desired acid (B); 4-nitro-2-benzyloxybenzoic acid 76 then esterified in step HI to produce the corresponding tertiary-aminoalkyl 4-nitro-2-benzyloxybenzoate (C) which in stepIV is reduced to the corresponding tertiaryaminoalkyl 4-amino-2-benzyloxybenzoate (D). Then, in step V, the tertiary-aminoalkyl 4-amino-2-hydroxybenzoate (E) is produced by catalytically debenzylating the basic 4-amino-2-benzyloxybenzoate (D). Steps IV and V can be carried'out in the same reaction vessel without isolating compound D when the reduction is carried out catalytically, e. g. as with palladium on charcoal. As a specific illustration of steps III, IV and V, 4-nitro-2-benzyloxybenzoic acid is esterified to produce 3-(2-methyl- 1-piperidyl)propyl 4-nitro-2-benzyloxybenzoate which is then reduced to the corresponding 3-(2-methyl-l-piperidyl)propyl 4-amino-2-benzyloxybenzoate, which, in turn, is reduced to 3-(2-methyl-1-piperidyl)propyl 4-amino- 2-hydroxybenzoate. y

We carried out estcrification step III by twovariants: home, the 4-nitro-2-benzyloxybenzoic acid was reacted with a tertiary-aminoalkyl halide; and in the other, said acid was first converted into the corresponding acid chloride which was then treated with a tertiary-aminoalkanol. The reduction step IV was carried out both by chemical 'methods and by catalytic hydrogenation. Suitable chemical reducing agents include iron and hydrochloric acid, ferrous sulfate, tin and hydrochloric acid, etc. We found iron and hydrochloric acid was to be preferred. Catalysts suitable when catalytic hydrogenation was employed include Raney nickel, platinum, palladium etc. Reduction step V was carried out by catalytic hydrogenation, using preferably palladium, although platinum and Raney nickel can be used, the latter at higher temperatures and pressures.

The tertiary-aminoalkyl 4-amino-2-benzyloxybenzoates (D) and the process (step V) of converting them into the corresponding 4-amino-2-hydroxybenzoates are disclosed and claimed in our copending application Serial Number 242,421, filed August 17, 1951, now Patent No. 2,662,888.

We claim:

1. A member of the group consisting of a basic ester having the formula O O O--X-N (lower alkyl) 1 where X is a lower alkylene radical having 2-4 carbon atoms. t r

3. An acid-addition salt of a basic ester having the formula 0-X-NR R where X is a lower alkylene radical having 2-4 carbon I 5 benzoic acid with a tertiary-aminoalkyl halide having atoms and NRR is a (lower alkylated)-l-piperidyl radical. V v 7 r 4. Anacid-addition salt of a basic ester having the formula 9. An acid-addition salt of 3-(1-piperidyl)propyl 4- amino-2-hydroxybenzoate.

10. A process of preparting a basic ester having the formula v COO-X-NRR' where NRR is a tertiary-amino radical selected from the group consisting of lower dialkylamino, l-piperidyl, (lower alkylated) -1-piperidyl, l-pyrrolidyl, ,(lower alkylated)-1-pyrrolidy1 and 4-morpholinyl and where X is a lower alkylene radical having 2-4 carbon atoms, which comprises reacting 4-nitro-2-hydroxybenzoic acid with a tertiary-aminoalkyl halide having the formula RRN'X-halogen and reducing the nitro group of the resulting tertiaryaminoalkyl 4-nitro-2-hydroxybenzoate.

11. A process of preparing a basic ester having the formula 0 0-X-N (lower alkyl): where X is a lower alkylene radical having 2-4 carbon atoms, which comprises reacting 4-nitro-2-hydroxythe formula (Lower alkyl)zNX-halogen and reducing the nitro group of the resulting dialkylaminoalkyl 4-nitro-2-hydroxybenzoate.

12. A process of preparing a basic ester having the formula OO-X-NRR' where X is a lower alkylene radicalhaving 2-4 carbon atoms and NRR is a (lower alkylated) -1-piperidyl radical, which comprises reacting 4-nitro-2-hydroxybenzoic acid with a tertiary-aminoalkyl halide having the formula RRN-X-halogen and reducing the nitro group of the resulting tertiaryaminoalkyl 4-nitro-2-hydroxybenzoate.

13. A process of preparing a basic ester having the formula where X is a lower alkylene radical having 2-4 carbon atoms and NRR' is a l-piperidyl radical, which comprises reacting 4-nitro-2-hydroxybenzoic acid with a tertiaryaminoalkyl halide having the formula RR'NX-halogen and reducing the nitro group of the resulting tertiaryaminoalkyl 4-nitro-2-hydroxybenzoate 14. A process of preparing Z-dimethylaminoethyl 4- amino-Z-hydroxybenzoate which comprises reacting 4- nitro-Z-hydroxybenzoic acid with a Z-dimethylaminoethyl halide and reducing the nitro group of the resulting Z-dimethylaminoethyl 4-nitro-2-hydroxybenzoate.

15. A process of preparing 3-(2-methyl-1-piperidyl).- propyl 4-amino-2-hydroxybenzoate which comprises reacting 4-nitro-2-hydroxybenzoic acid with a 3-(2-methyl- 1-piperidyl)propyl halide and reducing the nitro group 10 of the resulting 3-(Z-methyl-l-piperidyl)propyl 4-nitro- Z-hydroxybenzoate.

16. A process of preparing Z-diethylaminoethyl 4- amino-Z-hydroxybenzoate which comprises reacting 4- nitro-Z-hydroxybenzoic acid with a 2-diethylaminoethyl halide and reducing the nitro group of the resulting 2- diethylaminoethyl 4-nitro-2-hydroxybenzoate.

17. A process of preparing 3-diethylaminopropyl 4- amino-2-hydroxybenzoate which comprises reacting 4- nitroQ-hydroxybenzoic acid with a 3-diethylaminopropyl halide and reducing the nitro group of the resulting 3- diethylaminopropyl 4-nitro-2-hydroxybenzoate.

18. A process of preparing 3-(1-piperidyl)propyl 4- amino-Z-hydroxybenzoate which comprises reacting 4- nitro-Z-hydroxybenzoic acid with a 3-(1-piperidyl)propyl halide and reducing the nitro group of the resulting 3- l-piperidyl)propyl 4-nitro-2-hydroxybenzoate.

l9. 2-dimethylaminoethyl 4-arnino-2-hydroxybenzoate monohydrochloride.

20. 2 diethylaminoethyl 4 amino-Z-hydroxybenzoate monohydrochloride.

References Cited in the file of this patent UNITED STATES PATENTS 2,376,860 Blicke May 29, 1945 FOREIGN PATENTS 317,296 Great Britain Oct. 16, 1930 

1. A MEMBER OF THE GROUP CONSISTING OF A BASIC ESTER HAVING THE FORMULA
 4. AN ACID-ADDITION SALT OF A BASIC ESTER HAVING THE FORMULA 